The primary mission of the SRA is to understand the basic biological mechanisms, genetic and physiological risk factors, predictive diagnostic biomarkers, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This project will test the principal hypothesis that mutation of single genes co-expressed in brain, heart, and brainstem central autonomic neurons increase SUDEP risk by promoting cardiorespiratory arrhythmias. We will identify and validate novel ictal bradycardia and SUDEP gene candidates in mouse models to expand the SUDEP risk genome, and use modifier genes that suppress this risk in forebrain and brainstem autonomic circuits to genetically dissect critical SUDEP pathways. We will examine molecular excitability mechanisms perturbed by these genes in brain and heart, and the role of seizures and hypoxia in pathological network depolarization. We will also explore translational pharmacologic and genetic rescue strategies in these models. These findings will contribute to future genetic risk profiling for SUDEP in clinical exomes and point to new gene-directed approaches to reduce SUDEP in patients at high risk.
The primary mission of the SUDEP Research Alliance is to increase our understanding of the basic biological mechanisms, genetic and physiological risk factors, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This study will search for genes expressed in the brain and heart that may increase the risk of cardiac arrhythmias. Further investigation of these genes in mouse models will examine the molecular excitability changes in brain circuits that regulate the heart rate and pattern of breathing, and explore pharmacological methods of reversing the defects to reduce the SUDEP risk.
|Aiba, Isamu; Wehrens, Xander H T; Noebels, Jeffrey L (2016) Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. Proc Natl Acad Sci U S A 113:E4895-903|
|Noebels, Jeffrey (2015) Pathway-driven discovery of epilepsy genes. Nat Neurosci 18:344-50|
|Noebels, Jeffrey L (2015) Single-Gene Determinants of Epilepsy Comorbidity. Cold Spring Harb Perspect Med 5:|
|Aiba, Isamu; Noebels, Jeffrey L (2015) Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med 7:282ra46|
|Lhatoo, Samden; Noebels, Jeffrey; Whittemore, Vicky et al. (2015) Sudden unexpected death in epilepsy: Identifying risk and preventing mortality. Epilepsia 56:1700-6|
|Qi, Yitao; Wang, Jingxiong; Bomben, Valerie C et al. (2014) Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death. Neuron 83:1159-71|